The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection

Abstract

Cytoplasmic and endosomal RNA sensors recognize RNA virus infection and signals to protect host cells by inducing type I IFN. The cytoplasmic RNA sensors, retinoic acid inducible gene I/melanoma differentiation-associated gene 5, actually play pivotal roles in sensing virus replication. IFN-β promoter stimulator-1 (IPS-1) is their common adaptor for IFN-inducing signaling. Toll/IL-1R homology domain-containing adaptor molecule 1 (TICAM-1), also known as TRIF, is the adaptor for TLR3 that recognizes viral dsRNA in the early endosome in dendritic cells and macrophages. Poliovirus (PV) belongs to the Picornaviridae, and melanoma differentiation-associated gene 5 reportedly detects replication of picornaviruses, leading to the induction of type I IFN. In this study, we present evidence that the TLR3/TICAM-1 pathway governs IFN induction and host protection against PV infection. Using human PVR transgenic (PVRtg) mice, as well as IPS-1−/− and TICAM-1−/− mice, we found that TICAM-1 is essential for antiviral responses that suppress PV infection. TICAM-1−/− mice in the PVRtg background became markedly susceptible to PV, and their survival rates were decreased compared with wild-type or IPS-1−/− mice. Similarly, serum and organ IFN levels were markedly reduced in TICAM-1−/−/PVRtg mice, particularly in the spleen and spinal cord. The sources of type I IFN were CD8α+/CD11c+ splenic dendritic cells and macrophages, where the TICAM-1 pathway was more crucial for PV-derived IFN induction than was the IPS-1 pathway in ex vivo and in vitro analyses. These data indicate that the TLR3/TICAM-1 pathway functions are dominant in host protection and innate immune responses against PV infection.

3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

“…MDA-5 is generally thought to detect picornaviruses (48)(49)(50). However, evidence suggests a pivotal role for TLR3 and RIG-I as well (51)(52)(53)(54)(55). We recently reported that EV-D68 perturbs TLR3 via proteolytic cleavage of the TIR-domain-containing adapterinducing interferon-␤ (TRIF) adaptor (35).…”

Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA

“…In the case of PV infection, TLR3-mediated type I IFN production is important for viral clearance in vivo 15,16 . In vitro PV infection of splenic DCs promotes type I IFN production in a TLR3-dependent manner.…”

“…TLR3-or TICAM-1-deficient human PV receptor (PVR)-transgenic mice were more susceptible than normal PVR-transgenic mice to intraperitoneal or intravenous inoculation with a low titre of PV 15,16 . TLR3-dependent type I IFN production by splenic CD11c þ DCs and macrophages was essential for the protection of PVR-transgenic mice against PV infection.…”

“…Studies using TLR3-deficient mice demonstrated that TLR3 mediates a protective response against positive-strand RNA virus infection, including coxsackie virus group B serotype 3, encephalomyocarditis virus and poliovirus (PV), all of which belong to the Picornaviridae family [13][14][15][16] . TLR3-or TICAM-1-deficient human PV receptor (PVR)-transgenic mice were more susceptible than normal PVR-transgenic mice to intraperitoneal or intravenous inoculation with a low titre of PV 15,16 .…”

MAVS-dependent IRF3/7 bypass of interferon β-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells

“…Although TLR3/TICAM-1 participate in BMDC maturation in response to cell-derived virus RNA in RNA virus infections (Ebihara et al, 2008;Oshiumi et al, 2011), this is not the case in MV infection. , 2013).…”